Researchers identify new role for microglia in blood-brain barrier maintainence.


When the blood-brain barrier (BBB) is breached the brain becomes vulnerable to infection and injury. Therefore, it’s imperative that the openings in the BBB are resealed quickly. This most frequently occurs during a stroke, which triggers inflammation that can cause the BBB to break down.  When this barrier is breached it must be rapidly repaired in order to maintain the health of the brain and aid in recovery after an injury, a process that could be impaired by drugs that are intended to prevent this damage in the first place.  Now, a study from researchers at University of Rochester shows that the cells responsible for protecting the brain from infection and inflammation are also responsible for repairing the system of defenses that separates the brain from the rest of the body. The team state that their findings have significant clinical implications because certain cardiovascular drugs could possibly impede the brain’s ability to repair itself after a stroke or other injury.  The study is published in the journal Proceedings of the National Academy of Sciences.

Previous studies show that the brain is essentially an independent and separate ecosystem. Movement in and out of the brain is tightly controlled through a complex system of gateways and controls that are collectively referred to as the blood-brain barrier (BBB).  Microglia serve as the brain’s first responders and are present throughout the brain and spinal cord. These cells are constantly monitoring their environment, and can perform many functions such as controlling inflammation, destroying pathogens and cleaning up the debris from dead or damaged cells.  It is known that microglia are integral functional elements of the central nervous system, however, the contribution of these cells to the structural integrity of the neurovascular unit has not been assessed.  The current study shows that these resident immune cells play a critical and previously unappreciated role in maintaining the integrity of the blood-brain barrier.

The current study in mice shows that when small holes where made in the BBB, nearby microglia were rapidly mobilized and set about repairing the breach. Results show that in most instances, the integrity of the BBB was restored within 10 to 30 minutes.  Data findings show that the brain’s immune system, specifically cells called microglia, play a central role in the process of repairing damage to the BBB.

Results show that a receptor called P2RYX12 is responsible for activating the microglia and directing them to the site of the damage. The group state that the finding is significant because the same receptor is also present on platelets and is one of the targets of blood thinning drugs.  They go on to explain that these drugs are given to individuals at risk of heart attack and stroke and helps prevent platelets from binding together to form blood clots that, when they make their way to the brain, can block the flow of blood and trigger a stroke.

The team surmise that their findings are of importance as P2RY12 receptor antagonists also suppress P2RYX12 receptors in microglia and, therefore, potentially impair the ability of the brain to carry out repairs to the BBB once a stroke occurs.  For the future, the researchers are investigating the impact of P2RYX12-blocking drugs on microglia function in the brain.

Source: University of Rochester Medical Center (URMC)

 

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions. Reactive astrocytes promote breakdown of the blood-brain barrier in multiple sclerosis. Chapouly et al. demonstrate that astrocyte-derived VEGF-A and DDR, the enzymatic product of a newly recognised astrocyte-derived protein, endothelial cell growth factor-1/thymidine phosphorylase (ECGF1/TP), synergistically drive blood-brain barrier permeability in inflammatory brain lesions.

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions. Reactive astrocytes promote breakdown of the blood-brain barrier in multiple sclerosis. Chapouly et al. demonstrate that astrocyte-derived VEGF-A and DDR, the enzymatic product of a newly recognised astrocyte-derived protein, endothelial cell growth factor-1/thymidine phosphorylase (ECGF1/TP), synergistically drive blood-brain barrier permeability in inflammatory brain lesions.

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